The sesquiterpene endoperoxide lactone artemisinin and its 10.alpha. derivative dihydroartemisinin hemisuccinate are used in chemotherapy against ordinary and severe (acute) infections with Plasmodium falciparum, which is responsible for 85% of malarial illnesses. The chemistry and the antiprotozoal action of these compounds is described in the following publications: H. J. Woerdenbag et al., Progress in the Research of Artemisinin-related Antimalarials: An Update, Pharm. World Sci. 16 (4), 169-180 (1994); T. T. Hien et al., Qinghaosu, The Lancet 341, 603-608 (1993); A. R. Butler et al., Artemisinin (Qinghaosu): A New Type of Antimalarial Drug, Chem. Soc. Reviews 85-90 (1992); S. S. Zaman et al., Some Aspects of the Chemistry and Biological Activity of Artemisinin and Related Antimalarials, Heterocycles 32 (8), 1593-1638 (1991); H. J. Woerdenbag et al., Artemisia annua L.: a Source of Novel Antimalarial Drugs, Pharm. Weekblad Sci. 12 (5), 169-181 (1990); D. L. Klayman, Qinghaosu (Artemisinin): An Antimalarial Drug from China, Science 228, 1049-1055 (1985).
The water-insoluble dihydroartemisinin hemisuccinate is customarily administered orally in the form of tablets or rectally in the form of suppositories, while the water-soluble sodium salt (sodium artesunate) is administered intravenously.
Dihydroartemisinin hemisuccinate, together with a number of other 10-ester and 10-ether derivatives of dihydroartemisinin, was synthetically prepared for the first time by Chinese scientists at the end of 1979 to the beginning of 1980. D. Shaofeng et al., .sup.3 H Labeling of QHS Derivatives, Bull. Chin. Materia Medica 6 (4), 25-27 (1981) and Y. Li et al., Synthesis of Ethers, Carboxylic Esters and Carbonates of Dihydroartemisinin, Acta Pharm. Sin. 16 (6), 429-439 (1981) describe the preparation of dihydroartemisinin hemisuccinate by acylation of dihydroartemisinin with succinic anhydride in pyridine. In the last-mentioned publication, in which this process was presented as general method A.sub.1 for the preparation of various dihydroartemisinin 10-esters, it was possible to obtain the dihydroartemisinin hemisuccinate in a yield of 60% by means of warming dihydroartemisinin and succinic anhydride in pyridine at 30.degree. C. for 24 hours.
An improved version of the acylation of dihydroartemisinin, designated as method B.sub.1, was proposed by L. Ying et al. in The Synthesis of Some Carboxylic Esters and Carbonates of Dihydroartemisinin by Using 4-(N,N-Dimethylamino)pyridine as an Active Acylation Catalyst, Acta Chim. Sinica 40 (6), 557-561 (1982) and described in detail with the aid of the preparation of dihydroartemisinin-10-valerate. In this process, 2 mmol of dihydroartemisinin were dissolved in 30 ml of 1,2-dichloroethane and treated with 4 mmol of valetic anhydride, 0.33 mmol of 4-(N,N-dimethylamino)pyridine and 29 mmol of triethylamine, and the mixture was stirred at room temperature until dihydroartemisinin had been used up. The reaction mixture was then acidified with dilute hydrochloric acid and the aqueous phase was separated off. The oily residue, obtained after washing and drying the organic phase and distilling off the solvent, was purified by chromatography on silica gel using petroleum ether 60.degree.-90.degree./ethyl acetate 10:1 as eluent.
The use of this procedure for the preparation of the dihydroartemisinin hemisuccinate, but with dihydroartemisinin, succinic anhydride and 4-(N,N-dimethylamino)pyridine in the molar ratio 1:1.5:0.20 and a reaction time of 5 hours, afforded dihydroartemisinin hemisuccinate in a yield of 65%.
The known methods A.sub.1 and B.sub.1 for the acylation of dihydroartemisinin require the presence of organic bases, namely the presence of pyridine in method A.sub.1, and the presence of triethylamine and 4-(N,N-dimethylamino)pyridine in method B.sub.1. The use of organic bases in the acylation of alcohols with acyl halides or acyl anhydrides is customary practice, and it is known that organic bases can serve not only as catalysts, but also for the neutralization of the acid liberated during the acylation (cf. F. A. Carey and R. J. Sundberg, Advanced Organic Chemistry, Third Edition, Part A, page 476, Plenum Press, New York, 1991).
Until now, only these two Chinese methods A.sub.1 and B.sub.1 for the synthesis of the dihydroartemisinin hemisuccinate have been made public, which, however, are unsuitable for the preparation of larger amounts and not only are not very economical, but also would involve considerable technical and/or environmental problems with respect to the working up and disposal of the solvents, reagents and by-products. In particular, chromatographic separation is not practicable in the production of larger amounts. Furthermore, in the improved version B.sub.1 the use of pyridine as a solvent is in fact avoided, but 4-(N,N-dimethylamino)pyridine is employed as a catalyst and, as a solvent, 1,2-dichloroethane is used, which is ecologically not entirely acceptable and after distillation partly remains behind as contamination of the product. Moreover, comparatively large amounts of solvent and reagents are needed in the previously known process B.sub.1, namely 15 l of 1,2-dichloroethane and 14 mole of triethylamine per mole of dihydroartemisinin and furthermore a 50-100% excess of succinic anhydride.